More than 55,000 new cases of non-Hodgkin's lymphoma (NHL) are diagnosed each year in the United States, and it is the fifth most common cause of cancer death in the United States. Recent epidemiological data demonstrate that the incidence of this disease is increasing more rapidly than any other cancer except malignant melanoma. Mantle cell lymphoma (MCL) is a discrete entity that has the worst survival of any type of NHL (median 2-3 years). Most authorities believe that conventional chemotherapy and radiation regimens are not curative for advanced MCL. The objective of this research proposal is to conduct a pilot Phase I clinical trial testing a novel new immunotherapeutic approach for MCL using autologous T lymphocytes that have been genetically modified to express a chimeric T cell receptor recognizing the CD20 antigen present on B cell lymphomas. In Aim 1, we will assess the safety, feasibility, and toxicity of cellular immunotherapy in patients with relapsed CD20+ MCL utilizing ex-vivo expanded, autologous cytotoxic T cells genetically modified to express a CD20-specific scFvFc:zeta chimeric immunoreceptor that incorporates an SP163 translational enhancer as well as CD28 and CD137 co-stimulatory domains. Before T cell infusions, patients will undergo "lymphodepletion" of endogenous T cells with fludarabine to promote "homeostatic proliferation" of the adoptively transferred, genetically-modified CD20-specific T cells. In Aim 2, we will determine the duration of in vivo persistence of adoptively transferred CD20-specific T cells and their trafficking to lymph nodes and other tumor sites. Serial quantitative gamma camera imaging will be performed after infusion of 111lndium-tagged, genetically modified, anti-CD20 specific T cells. In addition, serial flow cytometry and quantitative PCR will be employed to monitor the persistence of infused T cells in the bloodstream and in tumor sites using bone marrow and LN biopsies. In Aim 3, we will monitor the development of humoral and cellular immune responses generated against the anti-CD20 chimeric T cell receptor and the NeoR selection gene product in patients undergoing adoptive T cell immunotherapy. The preliminary results obtained to date suggest that this novel immunotherapy represents a safe, promising approach for patients with relapsed MCL. [unreadable] [unreadable] [unreadable]